Autism spectrum disorders (ASDs also collectively referred to herein as autism) include a group of serious and enigmatic neurobehavioral disorders that usually become apparent early in childhood and persist as lifelong disabilities. Disturbances in three categories of behavior (reciprocal social interactions, verbal and nonverbal communications, and age appropriate activities and interests) are considered hallmarks of ASDs. The conditions encompassed in ASDs can have a tremendous impact on society and families as affected individuals utilize a wide range of services and considerable resources, particularly considering that patients diagnosed with autism often reach adulthood and require special assistance for their entire life span.
The number of children diagnosed with ASDs has greatly increased in recent decades. At the midpoint of the 20th Century, autism was narrowly defined and uncommonly diagnosed (with a prevalence of about four per 10,000). Greater awareness, availability of services, changes in diagnostic criteria to include a broader spectrum of neurodevelopmental abnormalities, and possibly other factors have contributed to the ten-fold or greater increase in the frequency with which ASDs are diagnosed. One extraordinary aspect of the epidemiology is the three-fold to six-fold excess of males. The prevalence of ASDs is currently considered to be about 1% in the U.S. population under 8 years of age.
ASDs appear causally heterogeneous, which makes clear understanding and diagnosis of the conditions more difficult. Although scientists have long abandoned the idea that autism is caused by humorless and rigid parenting, they have been unable to identify specific cause(s) in any substantial proportion of cases. Standardized criteria for autism as defined in the Diagnostic and Statistical Manual, IVth Edition (DSM IV-TR) may be assessed based on parental, caregiver, and/or examiner observations using the Autism Diagnostic Interview, Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS). Such diagnosis is typically not performed before the age of 3, even if recent progress has allowed diagnosis at an earlier age.
Only meager evidence exists to suggest that environmental insults play a significant role in the causation of autism. Prenatal and postnatal infections (rubella, cytomegalovirus, herpes) have been documented in a few cases. Little evidence exists to suggest injury in the perinatal period as a causative factor, although low birth weight and premature birth has been noted as a risk factor (Schendel, et al. 2008). Although autism has been reported among infants with prenatal exposure to thalidomide, cocaine, alcohol, and valproate, most infants prenatally exposed to these and other drugs or chemical agents do not develop autism.
The genetic contribution to the causation/predisposition to autism is considered to be substantial on the basis of high concordance in monozygous twins, a recurrence rate of about 5% among siblings, the uniquely high male:female ratio (about 4:1 in most studies), the co-occurrence of autism with a number of single gene disorders and chromosome aberrations, and the presence of behavioral disturbances among first degree relatives. These considerations aside, no single specific genetic cause has been found to explain more than 1-2% of autism cases, and overall only in 10-20% of autism cases can a cause be determined.
The strongest evidence for a heritable basis of autism comes from twin studies. Overall, these studies show high concordance of autism among monozygous (MZ) twins and low concordance among same sex dizygous (DZ) twins, resulting in greater than ninety percent heritability estimates. Four prominent studies dealing specifically with autistic disorders (narrowly defined to exclude Asperger disorder and Pervasive Developmental Disorder Not Otherwise Specified) report concordance of 36-96% in MZ twins and 0-30% in same-sex DZ twins (Folstein and Rutter 1977, Ritvo et al. 1985, Steffenburg et al. 1989, Bailey et al. 1995).
Chromosomal abnormalities have been found in a number of individuals with autism. These include marker chromosomes, microdeletions and microduplications, rearrangements, and autosomal fragile sites (Schroer et al. 1998, Ullmann et al. 2007, Morrow et al. 2008, Freitag 2007, Sebat et al. 2007, Weiss et al. 2008, Marshall et al. 2008). Taken together, these observations do not suggest a single underlying chromosomal aberration, but rather that a variety of chromosomal changes may disturb brain development and function in a way that leads to autism.
A number of genome-wide screens to identify chromosomal regions linked to autism susceptibility have been reported. However, the study of candidate genes within many of these linkage regions has failed to identify genes that clearly cause or strongly predispose to autism.
Although several X-linked genes have been associated with autism or autistic features in males, X-chromosomal loci have not been implicated in autism by linkage analyses. This may be explained in part by existence of multiple X loci of importance (heterogeneity) or by the uninformative nature of the sib-pairs used in the analysis. Of greater importance is that linkage analysis would not detect epigenetic modifications of gene(s) on the X chromosome.
The recurrence rate in brothers and sisters of affected persons is 3-8%. This recurrence rate is less than expected if all cases were caused by autosomal recessive gene mutations (25%) or autosomal dominant gene mutations (50%). The rate is not unlike that found in conditions considered to have multifactorial causation, such as neural tube defects and cleft lip/palate. Multifactorial causation implies collaboration between multiple genetic factors and environmental influences.
The various chromosomal alterations and gene mutations currently reported in association with autism indicate the genetically heterogeneous nature of autism and taken together account for only a minority (less than 20%) of cases. No laboratory finding has been consistently abnormal, although plasma serotonin levels may be elevated in affected individuals and first-degree relatives. James et al. (2006, 2008) have proposed that metabolic vulnerability to oxidative stress may be an autism susceptibility factor, and Carter (2007) has suggested that the skewed male:female ratio in autism may be explained by sex-specific responses to the neuropeptides, oxytocin and vasopressin.
As the underlying causes of ASDs remain elusive, and though several biochemical markers have been inconsistently associated with autistic traits (e.g., hypersertoninemia, urinary catabolites, and oxidative metabolism markers), there remains a need for a relatively simple laboratory test that can offer a reliable confirmation for the clinical diagnosis of ASDs and/or to provide a route for an efficient screening of individuals with autism. Because of the absence of consistent physical findings in autism and the uncertainty of the diagnosis in the first years of life, a laboratory test that helps diagnose autism, particularly at an early age, would be of great benefit.